Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension Helen J.L. Speirs a , Ksenia Katyk a , Natasha N. Kumar a , Adam V. Benjafield a , William Y.S. Wang b and Brian J. Morris a Objective: To perform association studies of polymorphisms of the potential candidate essential hypertension (HT) genes GRK4, PTP1B and HSD3B1. Methods: Subjects consisted of 168 unrelated, Caucasian essential hypertensive (HT) patients and 312 normotensive (NT) controls. Biological power was increased by ensuring subjects in each group had parents with the same blood pressure (BP) status as theirs. Three GRK4ª variants (R65L, A142V and A486V), one HSD3B1 variant (T C Leu 338 ) and one PTP1B variant (1484insG) were genotyped by polymerase chain reaction and restriction enzyme digestion or by homogenous MassEXTEND TM Assay. Results: The V allele of the A486V variant of GRK4ª, but not the R65L or A142V variants, showed an association with HT (P 0.02). The V allele was also associated with an elevation in systolic blood pressure (SBP) (P 0.002). Although the L65 and the V142 alleles tracked with elevation in diastolic (DBP), this was seen only in male HTs (P 0.009; P 0.002, respectively). Haplotype frequencies differed between the HT and NT groups, particularly for the R, V, V haplotype combination of R65L, A142V and A486V, respectively. Neither of the HSD3B1 or PTP1B variants were associated with HT. Conclusion: Genetic variation in GRK4ª was associated with HT in the subjects studied. J Hypertens 22:931–936 & 2004 Lippincott Williams & Wilkins. Journal of Hypertension 2004, 22:931–936 Keywords: 3–â hydroxysteroid dehydrogenase/delta isomerase type 1, essential hypertension, G protein-coupled receptor kinase 4, polymorphism, protein phosphatase 1B a Basic & Clinical Genomics Laboratory, School of Medical Sciences and Institute for Biomedical Research, The University of Sydney, Sydney, Australia and b Department of Medical Genetics, The University of Cambridge, Cambridge, UK. Sponsorship: This research was supported by a grant from the National Health and Medical Research Council of Australia. Correspondence and requests for reprints to B.J. Morris, Basic & Clinical Genomics Laboratory, School of Medical Sciences and Institute for Biomedical Research, Building F13, The University of Sydney, NSW 2006, Australia. Tel: +61 2 9351 3688; fax: +61 2 9351 2227; e-mail: brianm@physiol.usyd.edu.au Received 27 October 2003 Revised 3 December 2003 Accepted 13 January 2004 Introduction An ever-expanding repertoire of genes is being tested for involvement in the genetic basis of essential hyper- tension (HT). The present study tackled several novel potential candidates, these being the G protein-coupled receptor kinase 4 gene (GRK4), 3-â hydroxysteroid dehydrogenase/delta isomerase, type 1 gene (HSD3B1) and protein phosphatase 1B gene (PTP1B). The ratio- nale for testing these is as follows. G protein-coupled receptor kinases have been impli- cated in HT, as they are involved in the desensitization of G protein-coupled receptors including the D 1 recep- tor [1–3]. Dopamine exerts its natriuretic actions via D 1 -like and D 2 -like receptors located in the renal proximal tubule. In conditions of sodium excess locally produced dopamine acts on renal tubule cells to inhibit sodium reabsorption [4]. In humans with essential HT, there is a decrease in the responsiveness of the D 1 receptor in proximal tubules due to the uncoupling of the D 1 receptor from its G protein/effector enzyme complex [2,5]. Variants R65L, A142V and A486V of the ª isoform of GRK4 (GRK4ª) have been shown to increase GRK activity, resulting in increased serine phosphorylation of D 1 receptors and uncoupling of the receptor and its G-protein complex [5]. These finding make these variants of considerable interest in the molecular genetic basis of HT. There has been recent interest in HSD3B1 because of the essential role of hydroxysteroid dehydrogenase 3 â1 in the biosynthesis of steroid hormones including aldosterone [6]. It has been proposed that genetic variation in HSD3B1 could lead to an elevation in plasma aldosterone, with resultant increase in intra- vascular volume and HT [7]. In support of this possibility, a single nucleotide polymorphism (SNP) T!C silent substitution at codon 338 in exon 4 of HSD3B1 was reported recently to be associated with elevated blood pressure (BP) in a population of ! Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Original article 931 0263-6352 & 2004 Lippincott Williams & Wilkins DOI: 10.1097/01.hjh.0000098298.36684.3f